Staphylococcus aureus is the second leading cause of hospital-acquired bloodstream infections. In 2003, nearly 300,000 patients in US hospitals acquired an S. aureus infection, which accounted for nearly three million days of hospitalization, $9.5 billion in excess costs, and at least 12,000 inpatient deaths. Additionally, approximately 50% of the US population either persistently or intermittently carries a biofilm of S. aureus in their nose without experiencing any symptoms. Despite the lack of symptoms, nasal carriage of S. aureus is a well-known risk factor for developing a hospital-associated staphylococcal infection. Nasal carriers of S. aureus are three- to six-times more likely to acquire an S. aureus infection in the hospital, and, approximately 80% of the time, that infection is caused by the strain of S. aureus that lives in their nose. Based on infection rates and the prevalence of S. aureus nasal carriers, it has been estimated that eradicating S. aureus from the noses of surgical patients could save $4.5 billion a year in US hospital costs. The only FDA-approved treatment for nasal decolonization of S. aureus is 2% mupirocin. Clinical studies have shown that nasal decolonization decreases the number of infections contracted by S. aureus carriers, but resistance to mupirocin is becoming a concern. In vitro, the concentration of mupirocin required to inhibit growth of S. aureus increases significantly after only one exposure, and there is a growing body of clinical evidence linking mupirocin resistance to unsuccessful nasal decolonization. Nitric oxide, a free radical gas naturally produced by the human body to help fight infection, is a promising alternative to mupirocin for nasal decolonization of S. aureus. In recent years, the use of nitric oxide as an antimicrobial agent has been investigated due to its broad-spectrum antimicrobial activity, ability to diffuse directly through cell membranes, and the belief that it would be very difficult for nitric oxide-resistant strains of bacteria to develop. Additionally, nitric oxide has been shown to be effective against biofilm embedded bacteria. The goal of this SBIR project is to use Novan's proprietary nitric oxide-releasing technology to develop a topical nitric oxide-releasing nasal product capable of eradicating S. aureus biofilms from the noses of carriers without breeding bacterial resistance. In this proposal, Novan aims to: 1) Establish the minimum concentration of nitric oxide-releasing silica (Nitricil(tm)) required for bactericidal activity against 90% of S. aureus clinical isolates under planktonic and biofilm growth conditions in vitro; 2) Determine whether S. aureus can develop stable resistance to nitric oxide; and 3) Evaluate the safety of Nitricil(tm) particles for use in the nose. Upon achieving these aims, Phase II efforts will focus on preclinical evaluation of intranasal Nitricil(tm) formulations, including: 1) testing the lead formulations against a mouse model of S. aureus nasal colonization; 2) full preclinical toxicology; and 3) the quality scale-up manufacturing of both drug substance and drug product required to submit an Investigational New Drug application to the FDA.